RESUMEN
INTRODUCTION: Diabetes mellitus is associated with the development of carbonyl-oxidative stress (COS) and an increased risk of a cerebral hemorrhage. Vitamin D3 is considered an additional drug to have an impact on COS and proteolysis in the extracellular matrix. OBJECTIVE: The study aimed to evaluate the impact of D3 on the COS-markers and matrix metalloproteinases MMP2/MMP9 activity after acute intracerebral hemorrhage (ICH) in rats with experimental type 2 diabetes mellitus (Т2DM) compared to metformin (Met). METHODS: T2DM was induced in rats via the intraperitoneal injection of streptozotocin (STZ) and nicotinamide (NA), ICH - by microinjection of bacterial collagenase into the striatum. Rats were randomized into five groups: 1 - intact animals (n = 8), 2 - T2DM (n = 9); 3 - T2DM+ICH (n = 7); 4 - T2DM+ICH+Met (n = 7); 5 - T2DM+ICH+D3 (n = 7). Blood glucose, glycated hemoglobin, and oral glucose tolerance test (OGTT) were assessed using commercial kits. Advanced oxidation protein products (AOPP), protein carbonyls (PC370/430), and ischemia-modified albumin (IMA) were measured by spectrophotometry, advanced glycation end products (AGEs) by quantitative fluorescence, and matrix metalloproteinases MMP2/9 by gelatin zymography. RESULTS: D3 does not significantly affect the glucose level and OGTT in rats with T2DM+ICH. However, it reduces AOPP, PC, and AGEs, thus reducing the COS index. In contrast, the activity of proMMP9 increases after D3 administration. These effects of D3 have been reported to be stronger and sometimes opposite to those of metformin. CONCLUSION: D3 supplementation may decrease the negative consequences of a cerebral hemorrhage in T2DM by reducing COS and preventing the accumulation of COS-modified proteins in the brain by regulating the expression and activity of MMP9.
Asunto(s)
Diabetes Mellitus Tipo 2 , Metformina , Ratas , Animales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Biomarcadores/metabolismo , Productos Avanzados de Oxidación de Proteínas/metabolismo , Productos Avanzados de Oxidación de Proteínas/farmacología , Colecalciferol/farmacología , Albúmina Sérica/metabolismo , Albúmina Sérica/farmacología , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/tratamiento farmacológico , Estrés Oxidativo , Hemoglobina Glucada , Metformina/farmacologíaRESUMEN
Albumin is one of the most abundant proteins in the body of mammals: about 40% of its pool is located in the intravascular space and the remainder is found in the interstitial space. The content of this multifunctional protein in blood is about 60-65% of total plasma proteins. A decrease in its synthesis or changes of functional activity can destabilize oncotic blood pressure, cause a violation of transporting hormones, fatty acids, metals, and drugs. Albumin properties change under ischemic attacks associated with oxidative stress, production of reactive oxygen species, and acidosis. Under these conditions, ischemia-modified albumin (IMA) is generated that has a reduced metal-binding capacity, especially for transition metals, such as copper, nickel, and cobalt. The method of determining the cobalt-binding capability of HSA was initially proposed to evaluate IMA level and then licensed as an ACB test for routine clinical analysis for myocardial ischemia. Subsequent studies have shown the viability of the ACB test in diagnosing other diseases associated with the development of oxidative stress. This review examines recent data on IMA generation mechanisms, describes principles, advantages, and limitations of methods for evaluation of IMA levels, and provides detailed analysis of its use in diagnostic and monitoring therapeutic efficacy in different diseases.